Bone marrow transplantation for Fanconi anemia

From bloodjournal.hematologylibrary.org by guest on July 14, 2011. For personal use only.

1995 86: 2856-2862

Bone marrow transplantation for Fanconi anemia E Gluckman, AD Auerbach, MM Horowitz, KA Sobocinski, RC Ash, MM Bortin, A Butturini, BM Camitta, RE Champlin and W Friedrich

Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.

From bloodjournal.hematologylibrary.org by guest on July 14, 2011. For personal use only.

Bone Marrow Transplantation for Fanconi Anemia By Eliane Gluckrnan, Arleen D. Auerbach, Mary M. Horowitz, Kathleen A. Sobocinski, Robert C. Ash, Mortimer M . Bortin, Anna Butturini, Bruce M . Carnitta, Richard E. Charnplin, Wilhelrn Friedrich, Robert A. Good, Edward C. Gordon-Smith, Richard E. Harris, John P. Klein, Juan J. Ortega, Ricardo Pasquini, Norma K.C. Rarnsay, Bruno Speck, Marcus R. Vowels, Mei-Jie Zhang, and Robert Peter Gale Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressivebone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bonemarrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomesof HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplantsforFanconianemiaperformed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabil-

From theInternational Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wl: the Hdpital St Louis, Paris, France; Rockefeller University, New York, NY; the Methodist Hospital of Indiana. Indianapolis, IN; the Midwest Children’s Cancer Center, Medical College of Wisconsin, Milwaukee, Wl: the M.D. Anderson Cancer Center, Houston, TX; the Universitat Kinderklinik, UldDonau, Germany; the All Children’s Hospital, St Petersburg, FL; the St George’s Hospital Medical School, London, UK; the Children’s Hospital Medical Center, Cincinnati, OH; the Hospital lnfantil Val1 d’Hebron, Barcelona, Spain; rhe Hospital de Clinicas, Curitiba. PR, Brazil; the University of Minnesota Hospital and Clinic, Minneapolis, MN; the Kantonsspital Basel, Basel, Switzerland; the Prince of Wales Children’s Hospital, Rundwick, Australia; Salick Health Care, L o s Angeles, CA. Submitted August 19, 1994; accepted June 6, 1995. Supported by Public Health Service Grant No. POI-CA-40053 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the US Department of Health and Human Services; and by grants from Alpha Therapeutic Corp, Armour Pharmaceutical CO, Astra Pharmaceutical, Bawter Healthcare Corp, Biogen. Lvnde and H a r p Bradley Foundation, Bristol-Myers Squibb CO, Frank G. Brotz Family Foundation, Burroughs- Wellcome Co. Center jbr Advanced Studies in Lrukemia, Charfes E. Culpeper Foundation, Eleanor Naylor Dana Charirable Trust, Epple)) Foundation for Research, Immunex Corp. Kettering Family Foundation. Kirin Brewery CO, Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Herbert H.Kohl Charities, Inc, Eli Lilly Company Foundation, Nuda and Herbert P. Mahler Charities, Marion Merrell Dow, Inc,Milstein Family Foundation, Milwaukee FoundatiodElsa Schoeneich Research Fund, Samuel RobertsNoble Foundation, Orrho Biotech Corp, John Oster Family Foundation, Elsa U. Pardee Foundation, Jane and Lloyd Pettit Foundution. Pharmacia, RGK Foundation, Roerig/Pfzer Pharmaceuticals, Sandoz Pharmuceuticuls, Walter Schroeder Foundation, Stackner Family Foundation, Sturr Foundation, Joan and Jack Stein Charities, and Wyeth-Ayerst Laboratories. Address reprint requests to M a y M . Horowitz, MD, MS, International Bone Marrow Transplant Registr?: Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. The publicationcosts of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordunce with I8 U.S.C. section 1734 solely to indicate this fact. 0 1995 by The American Society of Hematology. 0006-4971/95/8607-0042$3.00/0 2856

ities (95% confidence interval) of survival were 66% (58% to

73%) after HLA-identical siblings transplants and29% (18% to 43%) after alternative donor transplants. Youngerpatient age ( P .0001),higherpretransplant platelet counts ( P = .04), use of antithymocyte globulin ( P = .005), and useof low-dose (15 to 25 mgfkg) cyclophosphamide plus limited for pretransplant conditioning and field irradiation ( P = .OW) cyclosporine for graft-versus-host disease prophylaxis( P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especiallywhen there is an HLA-identical sibling donor. 0 1995 by The American Society of Hematology.

F

ANCON1 ANEMIA is an autosomal recessive disorder characterized by diverse congenitalabnormalities, progressive bone marrow failure, and increased risk of acute cancer^."^ The Fanconi myelogenousleukemiaandother anemia phenotype is variable; diagnosis based on clinical features is difficult and often unreliable.’ Hypersensitivity of Fanconi anemia cells to DNA cross-linking agents is a morereliable markerforthe Fanconi anemia genotype.‘ Lymphocytes from persons with Fanconi anemia haveincreasedchromosomebreaks eitherspontaneously or after incubationwith alkylatingagents such asdiepoxybutane (DEB) or nitrogen mustard.“’* Bone marrow transplantation is an effective therapy for Fanconianemia. Thereareseveral reports of successful transplants for Fanconi anemia, although most include few patients.”-15 Patient and disease factors affecting transplant outcome and optimal transplant approach are not well-defined. In particular, because Fanconi anemia patientsmay have increased sensitivity to cyclophosphamide and radiation in doses commonly used for pretransplant conditioning,“”’ some centers use lower doses to decrease transplant-related mortality.’x-21 Whether this strategy is effective is controversia~,l“.?’

This report from the International Bone Marrow TransplantRegistry (IBMTR) analyzes the outcome of 199 patients receiving bone marrowtransplants for Fanconi anemia from HLA-identical sibling (n = 15 1 ) or alternative related or unrelated donors (n = 48). We identify several patient, disease, andtreatment factors associated with transplant outcome. MATERIALS AND METHODS

Patients. Forty-two teams reported detailed information to the IBMTR for 228 patients receiving a bone marrow transplant for Fanconi anemia between 1978 and 1992. This study includes 199 patients whose lymphocytes showed increased chromosome breaks spontaneously or after exposure to cross-linking agents. Fifteen cases were excluded because cytogenetic analyses were not performed and 14 cases were excluded because no chromosome breaks were reported. One hundred fifty-one patients received transplants from Blood, Vol 86,No 7 (October l ) , 1995: pp 2856-2862

From bloodjournal.hematologylibrary.org by guest on July 14, 2011. For personal use only. 2857

BMT FOR FANCONI ANEMIA Table 1. Donor-Recipient Histocompatibilii and Relationship Donor

~

_ _ ~ ~ ~ HLA-identical sibling l-Antigen-mismatched sibling 2-Antigen-mismatched sibling HLA-identical parent l-Antigen-mismatched parent 2-Antigen-mismatched parent 3-Antigen-mismatched parent HLA-identical other relative l-Antigen-mismatched other relative 3-Antigen-mismatched other relative HLA-identical unrelated donor l-Antigen-mismatched unrelated donor Total patients

No.

~

151 3*

11 11 3

5* 25

1 2” 1

15 4

199

*One donor-recipient pair mismatched in rejection direction only (donor homozygous). t Two-antigen mismatch in rejection direction; l-antigen mismatch in GVHD direction. $ Two donor-recipient pairs mismatched in rejection direction only: 1 donor-recipient pair, 2-antigen mismatch in rejection direction, and l-antigen mismatch in GVHD direction; 1 donor-recipient pair, l-antigen mismatch in rejection direction, and 2-antigen mismatch in GVHD direction. § One donor-recipient pair mismatched in rejection direction only; 1 pair, 3-antigen mismatch in rejection direction, 2-antigen mismatch in GVHD direction.

HLA identical sibling donors, 29 from other related donors, and 19 from unrelated donors (Table 1). Patient, disease, and treatment variables studied are shown in Table 2. The median age at transplant was 10 years (range, 1 to 36 years). The median pretransplant level of granulocytes was 0.5 X 109L (range, < l to 4 X 109L) and median level of platelets was 26 X 109L (range, 2 to 305 X 109/L).At transplant, 8% of patients were untransfused, 50% had received fewer than 20 transfusions, and 42% had received 20 or more transfusions. Clinically important infections were present in 22% of patients in the week before transplant. Pretransplant conditioning regimens were divided into three main categories according to cyclophosphamide dose and radiation schedule. Forty-nine percent received limited field irradiation (LFI) plus low-dose (15 to 25 mg/kg) cyclophosphamide with or without antithymocyte globulin (ATG). The median LFI dose was 5 Gy (range, 4 to15Gy). Fifteen percent received totalbody irradiation (TBI) plus low-dose cyclophosphamide. The median TB1 dose was 6 Gy (range, 3 to 8 Gy). Fourteen percent of patients received high-dose ( 2 100 m a g ) cyclophosphamide with or without ATG andno radiation. The remainder (22%) received a variety of other conditioning regimens. Prophylaxis of graft-versus-host disease (GVHD) was with posttransplant methotrexate in 1l%, cyclosporine in 59%, methotrexate plus cyclosporine in 20%, T-cell depletion of donor bone marrow in 9%, and other regimens in 1% of patients. End points. The end points analyzed were graft failure, acute and chronic GVHD, interstitial pneumonia, and survival. Graft failurewas analyzed in patients surviving z 2 1 days after transplant using published riter ria^'.^^; persons who never engrafted as well as those with transient engraftment were considered to have graft failure. Acute GVHD was defined as moderate to severe (grade If-IV) disease using published ~ r i t e r i a ~patients ~ ~ * ~ ;surviving more than 21 days with engraftment were considered to be at risk. Chronic GVHD was determined by clinical criteria in patients survivinj more than 90 days with engraftment.” Interstitial pneumonia was defined as

nonbacterial pneumonia characterized by bilateral diffuse interstitial Statistical methods. Probabilities of graft failure, acute and chronic GVHD, interstitial pneumonia, and survival were calculated using the Kaplan-Meier method. The difference in survival between HLA-identical sibling and alternative donors was tested with the log-rank statistic. Associations between patient, disease, and treatment variables (Table 2) and survival were tested in multivariate analysis using Cox proportional hazards regression, with time-to-death as the outcome.29 A stepwise backward elimination procedure was used. Briefly, all covariates tobe considered were entered in an initial regression model. Factors not statistically significant ( P > .05) were removed from the model one at a time, with re-estimation of all model variables after each step. Variable elimination (or reinsertion) was stopped when all remaining factors were significant at a P value less than .05. The proportionality assumption was tested using a time-dependent covariate. Interactions were tested and none was significant. Potential center effects were tested using a center-specific frailty model.30In this approach, patients within a center share a common random effect that represents the shared unmeasured covariates for the center’s patients. This random effects model induces an association among individuals with a center. A Gamma frailty model including the covariates found significant in the final Cox model was fit tothe data. A testof the hypothesis of no shared random effect within centers was performed and found to be insignificant ( P = .9). This analysis strongly suggests that the simple Cox model provides a reasonable fit to the data and that there is no need for further adjustment for center effects once risk factors are accounted for. All P values are two-sided andbased on multivariate analysis, unless otherwise specified. Because of the large number of comparisons made, we considered only P values less than .O1 to be statistically significant.” P values between .01 and .05 are presented to show trends but should be interpreted with caution. This maybe overly conservative because the study includes 280% of the target population of patients receiving transplants for Fanconi anemia during the study period. RESULTS

Table 3 shows outcomes after HLA-identical sibling and alternative donor bone marrow transplants for Fanconi anemia. Two-year probabilities of survival (95% confidence interval) were 66% (58% to 73%) after HLA-identical sibling transplants and 29% (18% to 43%) after alternative donor transplants (Fig 1). A total of 109 of 199 patients are alive at a median of 33 months (range, 4 to 162 months) after transplantation. Ninety-nine of the 109 survivors (91%) have normal hematologic parameters and require no transfusions, 6 (6%) are improved compared with pretransplant hematologic values and require no or fewer transfusions, 3 (2%) are unchanged or worse, and hematologic parameters were not reported for 1 patient. At last follow-up, 91 % of survivors had Kamofsky performance scores 290%. Four patients developed cancers after transplantation. One patient developed acute myelogenous leukemia 4 months after transplantation, 2 patients developed squamous cell carcinoma of the tongue 6 and 7 years after transplantation, and 1 patient developed squamous cell carcinoma of the larynx 8 years after transplantation. Table 4 presents the results of a multivariate analysis of factors correlated with survival after HLA-identical sibling transplants after Fanconi anemia. Our main objective was


GLUCKMAN ET AL

Table 2. Patient, Disease, and Treatment Charactoristicsfor 199 Patients Receiving Bone Marrow Transplantsfor Fanconi Anemia, Accordingto Donor Type ~~

~

HLA-identical Sibling Donors (n = 151) No. of Patients Evaluable

Variable

at

(29)

Age diagnosis of Fanconi anemia (yr) 151 Family history of Fanconi anemia 45 137 No (67) Yes 13 Suspected (3) Age at 1st hematologic abnormality (yr) 6 ( l 0 yr GVHD prophylaxis CSA 2 MTX 2 other 110 10 MTX t other Conditioning included ATG No 95 Yes 25 Platelets pretransplant s26.5 X 109/~ 60 >26.5 X 109/~ 60 Conditioning (other than ATG) (1-14 75 LFI,Cy 15-25 mg/kg 20 TBI, Cy 15-25 mglkg 25 No radiation, Cy 2100 mg/kg

0 (3-18) 8

(2-14) 5 2 (1-9) 1)

0 4 ( 1-24)

Only non-T-cell-depleted cases with the conditioning regimens shown are included. Values are percentages. Abbreviations: Cl, confidence interval: IPn, interstitial pneumonia; CsA, cyclosporine: MTX, methotrexate; Cy, cyclophosphamide.

From bloodjournal.hematologylibrary.org by guest on July 14, 2011. For personal use only. BMT FOR FANCONI ANEMIA

ient cells 4 months after transplantation. It is possible that this patient had leukemia or myelodysplasia before transplantation. Three other patients developed squamous cell carcinomas. All 4 patients received L H for conditioning and the cancers occurred outside the radiation field. Posttransplantation tumors are also reported in another series among patients not receiving radiati~n.’~ Much longer follow-up is required to determine the risk of posttransplantation cancers and whether radiation increases risk. The use of cyclosporine with or without methotrexate for GVHD prophylaxis was also associated with a higher rate of survival, a finding similar to one observed in a recent IBMTR study of transplants for leukemia.39 Our data indicate that bone marrow transplants are effective in Fanconi anemia. An important question is when they should be performed. This issue is best addressed in a prospective study. However, the adverse impact of increasing age and lower pretransplantation platelet counts favors earlier intervention, especially when there is an HLA-identical sibling donor. REFERENCES 1. Fanconi G: Familial constitutional panmyelocytopathy Fanconi

anemia: Clinical aspects. Semin Hematol 4:233, 1967 2. Schroeder TM, Tilgen D, Kruger J, Vogel F Formal genetics of Fanconi anemia. Hum Genet 32:257, 1976 3. Auerbach AD, Allen RG: Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi Anemia Registry. Cancer Genet Cytogenet 51:1, 1991 4. Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD: Hematologic abnormalities in Fanconi anemia. An International Fanconi Anemia Registry study. Blood (in press) 5. Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD: The need for more accurate and timely diagnosis in Fanconi anemia. A report from the International Fanconi Anemia Registry. Pediatrics 91:1116, 1993 6. Auerbach AD: Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol 21:731, 1993 7. Sasaki MS, Tonomura A: A high susceptibility of Fanconi anemia to chromosome breakage by DNA cross-linking agents. Cancer Res 33:1829, 1973 8. Auerbach AD, Wolman SR: Susceptibility of Fanconi anaemia fibroblasts to chromosome damage by carcinogens. Nature 261:494, 1976 9. Auerbach AD, Adler B, Chaganti RSK: Prenatal and postnatal diagnosis and carrier detection of Fanconi anemia by a cytogenetic method. Pediatrics 67: 128, 1981 10. Berger R, Bernhelm A, Gluckman E: In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol 45:565, 1980 1 1. Berger R, Bemhelm A, Le Conlat M, Vecchione D, Schaison G: Nitrogen-induced chromosome breakage. A tool to Fanconi anemia diagnosis. Cancer Genet Cytogenet 2:269, 1980 12. Auerbach AD, Rogatko A, Schroeder-Kurth TM: International Fanconi Anemia Registry: Relation of clinical symptoms to diepoxybutane sensitivity. Blood 73:391, 1989 13. Gluckman E, Devergie A, Schaison G, Bussel A, Berger R, Sohier J, Bernard J: Bone marrow transplantation in Fanconi anemia. Br J Haematol 45:557, 1980 14. Flowers MED, Doney KC, Storb R, DeegHJ, Sanders JE, Sullivan KM, Bryant E, Witherspoon RP, Appelbaum FR, Buckner CD, Hansen JA, Thomas ED: Marrow transplantation for Fanconi

2861

anemia with or without leukemic transformation: An update of the Seattle experience. Bone Marrow Transplant 9167, 1992 15. Di Bartolomeo P, Di Girolamo G, Olioso P, Angrilli F, Dragani A, Palka G, Guanciali-Franchi P, Ciancarelli M, Papalinetti G, Fioritoni G, D’Antonio D, Iacone A, Torlontano G: Allogeneic bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant 10:53, 1992 16. Auerbach AD, Adler B, O’Reilly RJ, Kirkpatrick D, Chaganti RSK Effect of procarbazine and cyclophosphamide on chromosome breakage in Fanconi anemia cells: Relevance to bone marrow transplantation. Cancer Genet Cytogenet 9:25, 1983 17. Dutreix J, Gluckman E: Skin test of radiosensitivity. Application to Fanconi anemia. J Eur Radiother 4:3, 1983 18. Gluckman E, Devergie A, Dutreix J: Radiosensitivity in Fanconi anaemia: Application to the conditioning for bone marrowtransplantation. Br J Haematol 54:431, 1983 19. Gluckman E: Bone marrow transplantation for Fanconi anemia. Clin Haematol 2:153, 1989 20. Hows JM, Chapple M,Marsch JCW, Durrant S, Vin JL, Swirsky D: Bone marrow transplantation for Fanconi anaemia: The Hammersmith experience 1977-1989. Bone Marrow Transplant 4:629, 1989 21. Socie G, Gluckman E, Raynal B, Petit T, Landman J, Devergie A, Brison 0: Bone marrow transplantation for Fanconi anemia using low-dose cyclophosphamide/ thoracoabdominal irradiation as conditioning regimen: Chimerism study by the polymerase chain reaction. Blood 82:2249, 1993 22. Flowers M, Zanis I, Storb R, Pasquini R, Deeg J, Ribeiro R, Sanders J, Bryant E, Sullivan K, Appelbaum F:Bonemarrow transplantation in 32 patients with Fanconi’s anemia after conditioning with cyclophosphamide. Blood 82:344a, 1993 (abstr, suppl I ) 23. Champlin R E , Horowitz MM, vanBekkum DW, Camitta BM, Elfenbein GE, Gale RP, Gluckman E, Good RA, Rimm AA, Rozman C, Speck B, Bortin MM: Graft failure following bone marrow transplantation for severe aplastic anemia: Risk factors and treatment results. Blood 73:606, 1989 24. Gluckman E, Horowitz MM, Champlin RE, Hows JM, Bacigalupo A, Biggs JC, Camitta BM, Gale RP, Gordon-Smith EC, Marmont AM, Masaoka T, Ramsay NKC, Rimm AA, Rozman C, Sobocinski KA, Speck B, Bortin MM: Bone marrow transplantation for severe aplastic anemia: Influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome. Blood 79:269, 1992 25. Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA, Gluckman E, Good RA, Hoffmann RG, Kay HEM, Kersey JH, Marmont A, Masaoka T, Rimm AA, van Rood JJ, Zwaan FE: Risk factors for acute graft-vs-host disease. Br J Haematol 67:397, 1987 26. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED: Clinical manifestations of graftversus-host disease inhuman recipients ofmarrow from HLAmatched sibling donors. Transplantation 18:295, 1974 27. Atkinson K, Horowitz MM, Gale RP,vanBekkumDW, Gluckman E, Good RA, Jacobsen N. Kolb H-J, Rimm AA, RingdCn 0, Rozman C, Sobocinski KA, Zwaan FE, Bortin MM: Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 75:2459, 1990 28. Weiner RS, Horowitz MM, Gale RP, Dicke KA, van Bekkum DW, Masaoka T, RamsayNKC,Rimm AA, Rozman C, Bortin MM: Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia. Br J Haematol 71:535, 1989 29. Cox DR: Regression models and life tables. J R Stat SOCB 34:187, 1972 30. Klein JP: Semiparametric estimation of random effects using the Cox model based on the em algorithm. Biometrics 48:795, 1992 31. Smith DG, Clemins J, Crede W, HarveyM, Gracely ET:


Impact of multiple comparisons in randomized clinical trials. Am J Med 83545, 1987 32. Alter BP: Leukemia and preleukemia in Fanconi’s anemia. Cancer Genet Cytogenet 58:206, 1992 33. Auerbach AD: Leukemia and preleukemia in Fanconi anemia. Cancer Genet Cytogenet 58:209, 1992 34. Bortin MM, Rimrn AA: Severe combined immunodeficiency disease. Characterization of the disease and results of transplantation. JAMA 238591, 1977 35. Bortin MM, Gale RP, Rimm AA: Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA 245:1132, 1981 36. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, Hoffmann RC, Jacobsen SJ, Marmont AM, McGlave PB, Messner HA, Rimm AA, Rozman C, Speck B, Tura S, Weiner RS, Bortin MM: Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk for

GLUCKMAN ET AL

relapse associated with T-cell depletion. Ann Intern Med 108:806, 1988 37. Barrett AJ, Horowitz MM, Gale RP, Biggs JC, Camitta BM, Dicke KA, Gluckman E, Good RA, Herzig RH, Lee MB, Marmont AM, Masaoka T, Ramsay NKC, Rimm AA, Speck B, Zwaan FE, Bortin MM: Marrow transplantation for acute lymphoblastic leukemia: Factors affecting relapse and survival. Blood 74:862, 1989 38. SociC G, Henry-Amar M, Cosset JM, Devergie A, Girinsky T, Gluckman E: Increased incidence of solid malignant tumors after bonemarrow transplantation for severe aplastic anemia. Blood 78:277, 1991 39. Ringden 0,Horowitz MM,Sonde1 P, Gale RP, Biggs JC, Champlin RE, Deeg €€I, Dicke K, Masaoka T, Powles RL, Rimm AA, Rozman C, Sobocinski KA, Speck B, Zwaan FE, Bortin MM: Methotrexate, cyclosporine or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia? Blood 81:1094, 1993